It is widely believed that the steps in the major metabolic pathways are known and that the control of flux through these pathways occurs at a very limited number of "rate limiting" steps. This concept has lead to the design of drugs to alter the kinetics of these "rate limiting enzymes". It has also led to attempts to alter metabolic pathways by altering the amounts of rate limiting enzymes using the techniques of molecular biology. To the dismay of many, such interventions often fail to alter the rates of the pathways under study. These failures have led to an increased awareness that "control" of pathway flux is distributed among many enzymes of a metabolic pathway and can vary from enzyme to enzyme depending upon conditions. Metabolic control theory predicts distribution of control among many enzymes of a pathway. However, actual demonstration and testing of such theories was technically difficult. We were the first laboratory to make the required measurements of flux, kinetic and thermodynamic constants of each step, and the levels of all substrates and products required to make such a formal analysis of flux control in a major metabolic pathway. We went on to show that ketone bodies can act in heart to overcome insulin resistance in heart. Since Dr. Kashiwaya left this laboratory, I have continued to collaborate with him and he, with others at the Department of Neurology of Tottori University in Yonago, Japan, have applied these insights from our previous work to investigate the effects of ketone bodies upon two neuronal culture models of the two most common degenerative neurological diseases. Alzheimer's disease was modeled by adding amyloid beta 1-42 to embryonic rat hippocampal neuronal cultures and Parkinson's disease was modeled by adding MPP+ to mesencephalic neuronal cultures. In both cases, ketone bodies protected neurons from death induced by these very different toxins. The ability of ketone bodies to protect neurons under these conditions offers the possibility of therapy of these very common diseases as well as other diseases resulting from failures in either glycolysis or mitochondrial energy generation. Discussions of the uses of ketone bodies in the treatment of neurological diseases including refractory epilepsy and insulin resistance such as Leprechaunism was held in a Rare Disease Meeting at NIH on May 3, 2000. Work on metabolic control was done in collaboration with the Dept of Biochemistry, U of Barcelona and the Harbor UCLA Research Institute and was directed this year toward the hexosemonophosphate pathway and the role of thiamine in certain cancers and appeared in Cascante M, Centelles JJ, Veech RL et al: Nutrition & Cancer 2000;36:150-4. As a result of this work, a meeting sponsored by the NIH Office of Rare Diseases was convened in May 2000 where the potential therapeutic uses of ketone bodies was discussed in a disparate group of diseases. These include: Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, Leprechaunism and other forms of insulin resistance and in the prevention of apoptosis of lung and subsequent multiple organ failure subsequent to hemorrhage and resuscitation. We are extending this work by examining the effects of ketone bodies upon cardiac function in the MDX mouse, an animal model of Duchenne's muscular dystrophy. This most common genetic disease, affecting about 1/1000 males results in immobility by about 10 years and death between 20-25, usually from heart failure. There is currently no therapy for this disease resulting from failure to synthesize dystrophin. Attempts to express dystrophin in patients and animals have failed. Using the the principles of metabolic control analysis, we have determined that lack of dystrophin results in a defect in glucose transport, similar to insulin resistance. Accordingly this defect should be treatable by mild ketosis. We are in the process of examining this hypothesis in the isolated working perfused heart. If our results are successful in this preparation, we shall proceed to try similar therapies in the MDX mouse model. The application of the principles of metabolic control analysis has been suggested as a fruitful approach to the analysis of the phenotype seen observed in a number of common polygenic disorders which have proven to be insoluble by the present method of human genetic analysis, see Strohman R: Science 2002;296:701-3. It was also the subject of meetings in October and November 2002.